Acta Pharm. 60 (2010) 427–443
Original research paper
DOI: 10.2478/v10007-010-0038-3
Silymarin-solid dispersions: Characterization and influence
of preparation methods on dissolution
DALWADI SONALI1,*
SONI TEJAL2
THAKKAR VAISHALI2
GANDHI TEJAL2
1 Ramanbhai Patel College of Pharmacy
Charotar University of Science and
Technology Changa-388421, India
2 Anand Pharmacy College
Anand-388001, India
Accepted October 25, 2010
The influence of preparation methodology of silymarin
solid dispersions using a hydrophilic polymer on the dissolution performance of silymarin was investigated. Silymarin solid dispersions were prepared using HPMC E
15LV by kneading, spray drying and co-precipitation methods and characterized by FTIR, DSC, XRPD and SEM.
Dissolution profiles were compared by statistical and model independent methods. The FTIR and DSC studies revealed weak hydrogen bond formation between the drug
and polymer, while XRPD and SEM confirmed the amorphous nature of the drug in co-precipitated solid dispersion. Enhanced dissolution compared to pure drug was
found in the following order: co-precipitation > spray drying > kneading methodology (p < 0.05). All preparation
methods enhanced silymarin dissolution from solid dispersions of different characteristics. The co-precipitation
method proved to be best and provided a stable amorphous solid dispersion with 2.5 improved dissolution compared to the pure drug.
Keywords: silymarin, HPMC, solid dispersions, kneading,
spray drying, co-precipitation, dissolution parameters
Seeds of milk thistle (Silybum marianum L. Gaertn, Asteraceae) have been used in
medicine for over 2,000 years. Silymarin (SLM), an antihepatotoxic phytocomplex, is a
mixture of flavonolignans which has been widely used as a therapeutic agent for a variety of acute and chronic liver diseases. Silymarin is practically insoluble in water; therefore, upon oral administration, its absorption rate in the gastrointestinal tract is low, providing only about 20 to 40 % bioavailability (1).
Several approaches have been attempted to improve oral bioavailability of silymarin, complexation with a phospholipid (2), formation of an inclusion complex with b-cyclodextrin and hydroxypropyl-b-cyclodextrin (3), solid dispersion with a hydrophilic
polymer such as PEG 6000 (4), selfmicroemulsifying systems (5), co-precipitates (6) and
a complex with crosslinked polymers (7).
* Correspondence; e-mail: sonali.dalwadi@yahoo.com
427
Unauthenticated
Download Date | 7/20/19 3:57 AM
D. Sonali et al.: Silymarin-solid dispersions: Characterization and influence of preparation methods on dissolution, Acta Pharm. 60
(2010) 427–443.
Solid dispersions describe a family of dosage forms whereby the drug is dispersed
in a biologically inert matrix of carriers such as polyethyleneglycol (PEG), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), crosslinked polymers, usually
with a view to enhance oral bioavailability (8). Cellulose derivatives are naturally occurring
polysaccharides ubiquitous in the plant kingdom (8). Hypromellose, short for HPMC, is
found in a variety of commercial products as an excipient for various purposes (8). In the
present study, HPMC, E 15LV was chosen as a polymeric carrier to improve dissolution
and bioavailability of several poorly soluble drugs such as carbamazepine (9), cetirizine
hydrochloride (10) and felodipin (11).
The aim of the present investigation was to enhance the rate of dissolution of silymarin from solid dispersions and to assess the effect of preparation methodologies on
the dissolution performance of solid dispersion.
EXPERIMENTAL
Materials
Silymarin powder (containing 78.7 % silymarin, 20.3 % silybin and isosilybin by
HPLC) was a gift of Microlabs (India), HPMC E 15LV grade was a gift of Colorcon India,
and methanol and dichloromethane AR grade were purchased from Atul Chemical, India. All other ingredients, solvents and reagents used were of analytical or pharmaceutical grade. Deionized double-distilled water was used throughout the study.
Solubility of silymarin
Solubility studies were performed by placing an excess amount of silymarin into
25-mL glass flasks containing HPMC E 15LV in 20 mL distilled water (0, 0.5, 1.0, 1.5, 2.0,
2.5, 3.0, 3.5, 4.0 and 5.0 % (m/V)). All flasks were stoppered and kept shaking at 100 rpm
for 24 h in an Orbital Shaking Incubator (REMI, RIS24BL, India) at 37 °C. After equilibrium was achieved after 72 h, 5 mL of supernant was withdrawn, filtered through Whatmann filter paper (No. 1) and analyzed using a UV-visible spectrophotometer (Shimadzu UV-1650, Japan) at 286 nm (3). Experiments were performed in triplicate.
Preparation of physical mixtures
Physical mixtures of silymarin and HPMC E 15LV in 1:1, 1:3 and 1:5 mass ratios were
prepared by mixing in geometric proportions, followed by passing through a 0.152-mm
aperture sieve with minimum abrasion. The samples were collected and kept at room
temperature in screw-capped glass vials until use.
Preparation of solid dispersions
Solid dispersions were prepared in 1:1, 1:3 and 1:5 mass ratios of silymarin to
HPMC E 15LV by various methods.
428
Unauthenticated
Download Date | 7/20/19 3:57 AM
D. Sonali et al.: Silymarin-solid dispersions: Characterization and influence of preparation methods on dissolution, Acta Pharm. 60
(2010) 427–443.
Kneading method. – Silymarin and HPMC E 15LV were physically mixed, wetted
with water and kneaded thoroughly for 30 minutes in a glass mortar. The paste formed
was dried completely at 80 °C for 6 h, pulverized and passed through a 0.152-mm aperture sieve with minimum abrasion. The samples were collected and kept at room temperature in screw-capped glass vials until use.
Spray drying method. – HPMC E 15LV was dissolved in methanol/dichloromethane
(50:50, V/V) and silymarin was incorporated to get 5 % (m/V) of total solids in the solution. The resultant solution was evaporated using a Lab Spray Dryer (LABULTIMA,
LU-222 Advanced, India) at inlet temperature of 80 °C, maximum aspiration (99), pumping 45 % and feeding rate of 2.5 mL min–1 of HPMC E 15 LV solution. The samples were
collected and kept at room temperature in screw-capped glass vials until use.
Co-precipitation method. – HPMC E 15LV was completely dissolved in methanol to
get 5 % (m/V) solution. Silymarin was incorporated, the solution stirred till a homogeneous mixture was formed. Water (in double methanol quantity) was added dropwise to
form the precipitate. Dispersion was stirred continuously up to 30 min. Dispersion obtained was dried completely at 80 °C for 6 h, pulverized and passed through a 0.152-mm
aperture sieve with minimum abrasion. The samples were collected and kept at room
temperature in screw-capped glass vial until use.
Characterization of solid dispersions
Characterization was performed for pure silymarin, pure HPMC E 15LV, physical
mixtures and solid dispersions prepared by kneading, spray drying and co-precipitation.
FTIR spectroscopy. – IR-spectroscopy was conducted using a FTIR spectrophotometer (Spectrum GX-FT-IR, Perkin Elmer, USA) and the spectra were recorded in the wavelength region of 4000–400 cm–1. The procedure consisted of dispersing the samples in
KBr and gentle grinding to prepare pellets.
Differential scanning calorimetry (DSC). – DSC was performed using a differential
scanning calorimeter (DSC-PYRIS-1, Phillips, the Netherlands) to study the thermal behaviour of samples. The samples were heated in hermetically sealed aluminium pans at
a scanning rate of 10 °C min–1 from 50 ± 0.2 to 550 ± 0.2 °C. An empty aluminium pan
was used as a reference.
X-ray powder diffraction (XRPD). – X-ray diffraction study was carried out to characterize the physical form of silymarin in selected samples. The sample was allowed to
spread on the glass slide in approximately 0.5 mm thickness. The slide was then placed
vertically at 0° angle in the X-ray diffractometer (X"Pert Model, Philips) so that the X-ray
beam fell on it. The results were recorded over a range of 0–90° (2q) using a Cu-target
X-ray tube and Xe-filled detector. The conditions were: voltage 40 kV, current 20 mA,
room temperature, scintillation counter detector, non-rotating sample holder.
Scanning electron microscopy (SEM). – Surface characteristics of the samples were studied by SEM from 100 to 650x magnifications. A double sided carbon tape was affixed
onto aluminium stubs. The powder sample was sprinkled onto the tape. The aluminium
429
Unauthenticated
Download Date | 7/20/19 3:57 AM
D. Sonali et al.: Silymarin-solid dispersions: Characterization and influence of preparation methods on dissolution, Acta Pharm. 60
(2010) 427–443.
stubs were placed in the vacuum chamber of a scanning electron microscope (XL 30
ESEM with EDAX, Philips). The samples were observed for morphological characteristics using a gaseous secondary electron detector (XL 30, Philips) with working pressure
of 0.8 Pa and acceleration voltage of 30.00 kV.
In vitro dissolution study
The in vitro dissolution studies were carried using USP II (12) apparatus in 900 mL
of distilled water, 0.1 mol L–1 HCl and phosphate buffer pH 6.8, thermostatically maintained at 37 ± 0.5 °C at a rotation speed of 50 rpm. Silymarin, all solid dispersions and
physical mixtures, each containing an equivalent of 70 mg of silymarin, were subjected
to dissolution. At predetermined time intervals, 5 mL of dissolution medium was withdrawn and filtered through Whatmann filter paper (No. 1). The same volume was replaced with fresh medium. Samples were suitably diluted and analyzed spectrophotometrically at 286 nm. Each test was performed in triplicate.
Dissolution parameters
Dissolution efficiency (%). – Dissolution efficiency (DE) represents the area under the
dissolution curve at time t (measured using the trapezoidal rule) and expressed as percentage of the area of the rectangle described by 100 % dissolution in the same time (13):
t
DE = ∫
0
y × dt
× 100 %
y100 × t
where y is the drug percent dissolved at time t.
Mean dissolution time (MDT). – The MDT values (in min) were calculated from dissolution data using the equation:
n ∧
MDT =
∑t
j
DMj
j=1
n
∑ DM
j
j=1
∧
where j is the sample number, n is the number of dissolution sample times, tj is the time
at midpoint between tj and tj–1 [easily calculated with the expression (tj + tj–1) / 2] and
DMj is the additional amount of drug dissolved between tj and tj–1 (13).
Similarity factor f2 and dissimilarity factor f1. – A model-independent approach proposed by Moore and Flanner (14) for calculating f1 and f2 was used for comparison of the
dissolution profiles of various samples and was defined by the following equations:
430
Unauthenticated
Download Date | 7/20/19 3:57 AM
D. Sonali et al.: Silymarin-solid dispersions: Characterization and influence of preparation methods on dissolution, Acta Pharm. 60
(2010) 427–443.
n
f1 =
∑R
j
− Tj
j=1
× 100
n
∑R
j
j=1
2

n

 
f 2 = 50 log  1 + 1/ n∑ R j − Tj  


j=1
  
 
−0 . 5


× 100

in which n is the number of withdrawal points, Rj and Tj are the percent of the dissolved
reference and test products at each time point j.
Stability
Stability of solid dispersions was tested at 40 ± 2 °C and 75 ± 5 % RH for a period of
6 months. The samples were withdrawn at intervals of 15, 30, 60, 90 and 180 days and
were evaluated for the drug content and in vitro drug release. Percentage drug decomposition and any change in a dissolution profile were evaluated using fit factors (f1 and f2
factors).
RESULTS AND DISCUSSION
Solubility of silymarin
In the present investigation, solubility of silymarin in distilled water was found to
be 0.25 ± 0.004 mg mL–1. The solubility plot of silymarin in HPMC E 15LV (see Fig. 1)
shows that a 2.7 fold increase in solubility was found in 3 % HPMC E 15LV compared to
solubility in water. As the concentration of HPMC increased from 3 to 5 %, silymarin
solubility decreased, possibly due to the increase in solution viscosity (8) (Table I).
0.8
Silymarin (mg mL–1 )
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.0
1.0
2.0
3.0
4.0
HPMC E 15LV (%, m/V)
5.0
6.0
Fig. 1. Solubility plot of silymarin
in HPMC E 15LV.
431
Unauthenticated
Download Date | 7/20/19 3:57 AM
D. Sonali et al.: Silymarin-solid dispersions: Characterization and influence of preparation methods on dissolution, Acta Pharm. 60
(2010) 427–443.
The values of Gibb’s free energy change (DG°tr) were calculated from the following
equation to understand the transfer process of silymarin from distilled water to aqueous
solution of HPMC E 15LV (15):
DG°tr = –2.303 RT log (S0/Ss)
in which S0/Ss is the ratio of the molar solubility of silymarin in an aqueous solution of
HPMC E 15LV to that in distilled water. The DG°tr values were all negative for HPMC E
15LV at various concentrations (Table I), indicating the spontaneous nature of silymarin
solubilization (15).
Characterization of solid dispersions
FTIR. – It is well known that vibrational changes can serve as a probe of intermolecular interactions in solid materials. Characteristic peaks of silymarin appeared at 3423.36
(-OH stretching vibration), 2935 (O-H stretching), 1639.6 (C=O stretching), 1511–1465
(skeleton vibration of aromatic C=C ring stretching), 1362 (-OH in plane bending), 1274.6
(C-O-C stretching), 995 (O-H out plane bending), 1029–1161 (in plane = C-H bending)
and 644–849 cm–1 (see Fig. 2) (8). All spectra of solid dispersions showed changes from
parent spectra, that is, of silymarin and HPMC. Possible interactions would have occurred between the -OH, C-O, and -O- groups of HPMC E 15LV and of polyphenolic moiety
of silymarin revealed through frequency changes of the respective functional group (7).
Table I. Solubility and DG°tr values of silymarin
HPMC E 15LV
(%, m/V)
a
b
Solubility of silymarin
(mg mL–1)a
–DG°tr
(J K–1 mol–1)b
0.0
0.254 ± 0.004
–
0.5
0.262 ± 0.001
–83.9
1.0
0.316 ± 0.001
–561.2
1.5
0.333 ± 0.002
–699.5
2.0
0.479 ± 0.021
–1632.3
2.5
0.567 ± 0.025
–2069.7
3.0
0.689 ± 0.009
–2573.6
3.5
0.482 ± 0.008
–1648.2
4.0
0.386 ± 0.011
–1075.8
5.0
0.371 ± 0.004
–891.4
Mean ± SD, n = 6.
DG°tr – Gibb’s free energy change
432
Unauthenticated
Download Date | 7/20/19 3:57 AM
D. Sonali et al.: Silymarin-solid dispersions: Characterization and influence of preparation methods on dissolution, Acta Pharm. 60
(2010) 427–443.
Fig. 2. FTIR spectra of: pure HPMC E 15LV, silymarin, physical mixtures (PM), solid dispersions
(KND – kneading, SPRAY D. – spray drying, COPPT – co-precipitation), bottom to top.
433
Unauthenticated
Download Date | 7/20/19 3:57 AM
D. Sonali et al.: Silymarin-solid dispersions: Characterization and influence of preparation methods on dissolution, Acta Pharm. 60
(2010) 427–443.
In the spectra of physical mixtures, characteristic peaks substantially corresponded
to the superimposition of the peaks of both components, silymarin and HPMC. The band
which appeared at 3000–3600 cm–1 (assigned to -OH stretching) in the spectrum of silymarin was found at higher frequency in the case of dispersions. This revealed the formation of H-bond between the drug and -OH group of HPMC E 15LV in dispersion (14).
The characteristic peaks at 1600–1300 and below 1300 cm–1 were found to change their
intensity in the following order: co-precipitated < spray-dried < kneaded solid dispersion, but the H-bond interaction which occurred in solid disperions resulted in lower
peak intensity (7, 15). The IR spectra also demonstrate disruption of the crystal lattice
(8). In fact, the splitting phenomenon in frequency regions below 1300 cm–1, a typical
feature of the crystal lattice present in silymarin, was still present in physical mixtures,
but its intensity was reduced in kneaded, spray-dried and co-precipitated solid dispersions.
DSC. – The DSC thermograms of silymarin, HPMC E 15LV, physical mixtures and
solid dispersions are shown in Fig. 3. There was a considerable shift in the endothermic
peaks in the kneaded solid dispersion and physical mixture (1:1 ratio). The maximum
shifted from 369.7 °C to 349.2 °C and 349.9 °C in thermograms of kneaded solid dispersion and physical mixture, respectively, depicting the change in the crystal form of the
drug (17). Due to low silymarin enthalpy (DH = 27.280 J g–1) found from thermograms,
the DSC technique could not be used for characterization of silymarin solid dispersion
since suppression and disappearance of peaks could not be identified in the thermogram
(Fig. 3).
XRPD. – XRPD pattern of silymarin, HPMC E 15LV, physical mixtures and solid dispersions prepared by different methods are shown in Fig. 4. Silymarin is crystalline, as
demonstrated by the sharp and intense diffraction peak at 2q of 72.3°. HPMC E 15LV
was found as an amorphous powder having no diffraction peak. Physical mixtures showed diffraction peaks consistent with the presence of crystalline silymarin. The lower
intensity of diffraction peaks of physical mixtures was the result of a dilution effect with
amorphous HPMC E 15LV (18). The intensity of peak height was found to be reduced at
2q = 72,3° in kneaded and spray dried solid dispersions as compared to silymarin. The
XRPD pattern of co-precipitated solid dispersion showed complete disappearance of the
diffraction peak at the same 2q value, confirming the existence of the amorphous form
of silymarin.
The relative degree of crystalinity (RDC) of all solid dispersions and physical mixtures at the same 2q value are shown in Table II. The rank order of the relative degree of
crystallinity in dispersions could be given as: spray dried > kneaded > co-precipitated
solid dispersions. Co-precipitation produced amorphous particles compared to the pure
drug, which might be responsible for improved dissolution of the drug (19).
SEM. – The representative photomicrographs of silymarin, HPMC E 15LV, physical
mixtures and solid dispersions prepared by different methods are presented in Fig. 5.
The image of silymarin revealed drug particles with a reduced specific surface area due
to some aggregation and agglomeration. Morphological images of HPMC E 15LV exhibited cylindrical shape and similar to fiber (20). The photomicrographs of physical mixtures showed individual particles of silymarin and carrier without any surface adsorption.
434
Unauthenticated
Download Date | 7/20/19 3:57 AM
D. Sonali et al.: Silymarin-solid dispersions: Characterization and influence of preparation methods on dissolution, Acta Pharm. 60
(2010) 427–443.
Fig. 3. DSC thermograms of: pure HPMC E 15LV, silymarin, physical mixtures (PM), solid dispersions (KND – kneading, SPRAY D. – spray drying, COPPT – co-precipitation), bottom to top.
435
Unauthenticated
Download Date | 7/20/19 3:57 AM
D. Sonali et al.: Silymarin-solid dispersions: Characterization and influence of preparation methods on dissolution, Acta Pharm. 60
(2010) 427–443.
Fig. 4. XRPD patterns of: pure HPMC E 15LV, silymarin, physical mixtures (PM), solid dispersions
(KND – kneading, SPRAY D. – spray drying, COPPT – co-precipitation), bottom to top.
436
Unauthenticated
Download Date | 7/20/19 3:57 AM
D. Sonali et al.: Silymarin-solid dispersions: Characterization and influence of preparation methods on dissolution, Acta Pharm. 60
(2010) 427–443.
Table II. Relative degree of crystallinity of physical mixtures and solid dispersions
Sample
Co-precipitation (1:3)
Spray drying (1:3)
Relative degree of crystalinity at 2q = 72.3°
–
0.68
Kneading (1:1)
0.20
Physical mixture (1:3)
0.35
Physical mixture (1:1)
0.25
Silymarin
1.00
HPMC E 15LV
–
RDC – relative degree of crystalinity [ratio of the peak height in solid dispersion and the peak height of
silymarin alone, at the same angle (11)].
In the case of kneaded solid dispersions, photomicrographs showed that silymarin
particles were physically adsorbed over the respective carrier and formed porous solid
dispersion particles with a hard surface having crevices and fissures. The morphological
Fig. 5. SEM of: a) drug (SLM), b) HPMC E 15LV, c, d) physical mixtures (1:1, 1:3) and e, f, g) solid
dispersions (kneading, spray drying and co-precipitation).
437
Unauthenticated
Download Date | 7/20/19 3:57 AM
D. Sonali et al.: Silymarin-solid dispersions: Characterization and influence of preparation methods on dissolution, Acta Pharm. 60
(2010) 427–443.
images of the spray-dried solid dispersion revealed that drug particles were distributed
uniformly on the surface of carrier. Therefore, size reduction and uniform adsorption of
the drug over carrier were found in solid dispersion prepared by spray drying (21). The
SEM photomicrographs of the co-precipitated solid dispersion showed fully amorphous
and porous nature with an irregular, coarser and hard surface full of crevices. The images further suggest the existence of an amorphous product with the presence of a single component in the solid dispersion (16).
In vitro dissolution and dissolution parameters
The in vitro dissolution profiles of pure silymarin, physical mixtures, and optimum
ratios in solid dispersions prepared by kneading, spray drying and co-precipitation in
distilled water (Fig. 6a), 0.1 mol L–1 HCl (Fig. 6b) and phosphate buffer pH 6.8 (Fig. 6c)
over a period of 90 min are shown. It was evident that the in vitro dissolution of pure
silymarin was very low in all dissolution media (drug released after 60 min was 46.8,
45.3 and 43.3 % in water, 0.1 mol L–1 HCl and PBS 6.8, resp.). The kneading, spray drying and co-precipitation methods improved silymarin dissolution within 90 min in all
three dissolution media. Co-precipitation method showed maximum dissolution enhancement as compared to other preparation methods (> 80 % silymarin was released within
10 min from solid dispersion in three different dissolution media). This suggests that
preparation methodology has an effect on drug dissolution improvement.
The drug release from physical mixtures after 10 min was enhanced compared to
pure silymarin in all dissolution media.
The value of DE10min for pure silymarin was enhanced in physical mixtures as well
as in solid dispersions prepared by different methods significantly (p < 0.05) (Table III).
Among the different preparation methodologies used, increased in the following order:
co-precipitation > spray drying > kneading.
The mean dissolution time (MDT) is a measure of drug release retarding ability of
the dosage form (15). The value of MDT in three dissolution media for pure silymarin,
physical mixtures and solid dispersions prepared by different methods is presented in
Table III. Dissolution efficiency of solid dispersions prepared by various methods
DE (%) after time (min)
Dissolution
medium
HCl (c = 0.1 mol L–1 )
Water
60
10
30
60
10
30
60
43.6
63.4
38.8
67.5
80.1
31.6
58.2
73.1
73.5
78.5
35.5
63.2
77.9
35.4
60.8
72.8
37.9
67.6
81.3
37.6
65.1
76.8
37.6
65.1
76.8
Co-precipitates (1:3)
44.8
77.8
87.5
43.1
76.1
87.6
42.6
74.3
86.3
Physical mixture (1:1)
26.0
49.4
66
36.8
62.8
72.5
39.6
67.3
79.8
Physical mixture (1:3)
25.6
49
65
34.8
59.8
69.6
39.0
66.6
78.6
Parameter
10
Silymarin
15.6
Kneading (1:1)
48.9
Spray drying (1:3)
30
PB pH 6.8
DE – dissolution efficiency
438
Unauthenticated
Download Date | 7/20/19 3:57 AM
D. Sonali et al.: Silymarin-solid dispersions: Characterization and influence of preparation methods on dissolution, Acta Pharm. 60
(2010) 427–443.
Cumulative drug release (%, m/V)
a)
Time (min)
Cumulative drug release (%, m/V)
b)
Time (min)
Cumulative drug release (%, m/V)
c)
Time (min)
Fig. 6. In vitro dissolution profiles of solid dispersions in: a) water, b) 0.1 mol L–1 HCl, c) PB pH 6.8
(Mean ± SD, n = 3).
439
Unauthenticated
Download Date | 7/20/19 3:57 AM
D. Sonali et al.: Silymarin-solid dispersions: Characterization and influence of preparation methods on dissolution, Acta Pharm. 60
(2010) 427–443.
Table IV. It is evident that higher silymarin release was obtained (MDT = 7.4–8.3 min).
The MDT value increased from spray drying to kneading. The physical mixtures also
showed a considerably lower MDT value compared to pure silymarin.
It is evident from dissimilarity and similarity factors that the release profiles of silymarin prepared by all methods were significantly different (exception: physical mixtures) from that of silymarin (Table IV). Co-precipitation method showed maximum dissimilarity (f1 value higher than 100) and therefore is the best method to improve dissolution of silymarin in all dissolution media.
Analysis of variance revealed that the drug release profiles of kneaded solid dispersion (1:1 drug to polymer ratio), co-precipitated (1:3 drug to polymer ratio) and spray
dried solid dispersion (1:3 drug to polymer ratio) were significantly different (p < 0.05)
from that of pure silymarin. They showed improved drug release compared to that of
pure drug and other ratios of the respective methods. It is evident that in vitro dissolution of silymarin from co-precipitated solid dispersion was also significantly different
(p < 0.05) from that of pure silymarin and physical mixtures in different dissolution media.
The improved dissolution of silymarin from solid dispersion prepared by kneading,
spray drying and co-precipitation was attributed to the solubilizing effect of the carrier.
The improvement of powder wettability could result from formation of a gel layer around
the drug substance particles modifying the hydrophobicity of surfaces (11). Solid dispersions using HPMC E 15LV became gelatinized in the dissolution media. The gelatinized
solid dispersion is constantly crushed by attrition during stirring and the finely gelatinized solid dispersion diffuses to bulk solution through the diffusion layer. Being water
retentive, gelatinized dispersion also increases drug wetting, which is attributable to the
increase in dissolution (8). In addition, other factors such as increased surface area, the absence of aggregation and agglomeration between hydrophobic drug particles, conversion of drug to the amorphous form and good dispersibility of the dispersed drug might
have also contributed to the observed increase in the dissolution rate of silymarin from
solid dispersions prepared by different methods (15).
Table IV. Dissolution parameters for solid dispersions prepared by various methods
Dissolution
medium
Dissolution
parameter
HCl (c = 0.1 mol L–1)
Water
MDT
(min)
f1
f2
MDT
(min)
f1
PB pH 6.8
f2
MDT
(min)
f1
f2
Silymarin
22.4
–
–
12.3
–
–
15.
–
–
Kneading (1:1)
18.3
60.2
30.0
13.7
60.1
29.4
17.4
32.5
39.9
Spray drying(1:3)
11.4
118.5
18.0
16.2
96.1
19.3
14.4
75.5
22.1
7.8
169.4
10.2
7.4
128.7
13.2
8.3
91.4
17.4
Physical mixture (1:1)
20.9
11.3
62.9
17.6
15.7
56.8
12.5
5.9
72.2
Physical mixture (1:3)
21.5
12.6
61.4
19.2
4.5
57.8
13.4
6.2
72.2
Co-precipitates (1:3)
MDT – mean dissolution time.
f1, f2 – dissimilarity and similarity factor.
440
Unauthenticated
Download Date | 7/20/19 3:57 AM
D. Sonali et al.: Silymarin-solid dispersions: Characterization and influence of preparation methods on dissolution, Acta Pharm. 60
(2010) 427–443.
Table V. Drug content and dissolution parameters of co-precipitated solid dispersion
during stability study
Day
15
0
30
60
90
180
Condition
Rooma Testb Rooma Testb Rooma Testb Rooma Testb Rooma Testb Rooma Testb
Silymarin
(%, m/m)
99.04 99.04 99.24 99.01 99.04 98.59 99.04 98.59 99.05 98.59 99.14 98.59
Dissolution parameter
f1
–
–
f2
–
–
0.19
0.19
0.19
0.19
0.19
0.024
0.19
0.45
0.192
0.98
96.18 93.83 96.18 94.72 96.18 96.18 96.18 91.29 96.18 96.38
25 ± 2 °C and 40 ± 5 % RH
40 ± 2 °C and 75 ± 5 % RH
f1 and f2 – dissimilarity and similarity factor
a
b
Stability
The silymarin content in solid dispersions was higher than 98 % (m/m) over a period of 15, 30, 60, 90 and 180 days and implies stability of prepared dispersions (Table
V). Difference in drug release between aged and freshly prepared dispersions was evaluated by similarity and dissimilarity factors (f1 and f2). The results indicate similarity in
the dissolution profile of dispersions over a period of 6 months.
CONCLUSIONS
In conclusion, preparation methodologies have an effect on the physicochemical
characteristics of the dispersion and rate of dissolution of silymarin. Aqueous solubility
of silymarin was favoured by the presence of HPMC 15LV and spontaneous drug solubilization was also confirmed by the negative value of Gibb’s free energy. Among various drug to polymer ratios, the most favourable condition was found in 1:1 for the kneading method and 1:3 for other methods. The reduced intensity without shifting of characteristic peaks justifies weak hydrogen bond formation between the drug and polymer.
The X-ray diffraction pattern clearly demonstrates reduction in crystallinity and formation of partial amorphism in dispersions prepared by kneading, spray drying or co-precipitation. SEM photographs also support the amorphism in solid dispersions. Preparation methodology clearly affects the dissolution parameters. Improvement in the rate of
dissolution can be attributed to the increased surface area, increased solubility and reduction in crystallinity. The increased dissolution rate observed in the case of physical
mixtures might be due to the close contact of HPMC with silymarin, which improves
wetting and dissolution or might be caused by one or more of the characterization factors mentioned previously. Statistical evaluation suggested enhancement in silymarin
dissolution in co-precipitation (2.5 fold) > spray drying (1.9 fold) > kneading (1.5 fold).
Mean dissolution time (in min) was as follows: 8.3 for co-precipitation, 14.2 for spray
drying and 17.4 for kneading.
441
Unauthenticated
Download Date | 7/20/19 3:57 AM
D. Sonali et al.: Silymarin-solid dispersions: Characterization and influence of preparation methods on dissolution, Acta Pharm. 60
(2010) 427–443.
Acknowledgements. – We thank to Microlabs (India), Ltd. and Colorcon India, Ltd. for
providing gratis samples.
REFERENCES
1. S. Ahmad and N. Dixit, Silymarin: a review of pharmacological aspects and bioavailability enhancement approach, Ind. J. Pharm. 39 (2007) 172–179; DOI: 10.4103/0253-7613.36534.
2. S. Abrol, T. Aman and K. O. Parkash, Comparative study of different silymarin formulations:
formulation, characterization and in vitro/in vivo evaluation, Curr. Drug Deliv. 2 (2005) 45–51;
DOI: 1567-2018/05 $50.00+.00.
3. P. D. Nakhat, R. A. Naidu, I. B. Babla, S. Khan and P. G. Yeole, Design and evaluation of silymarin-HP-b-CD solid dispersion tablets, J. Pharm. Sci. 69 (2007) 287–289; DOI: 10.4103/0250-474X.33160.
4. J. H. Hu and F. Q. Li, Improvement of the dissolution rate of silymarin by means of solid dispersions, Chem. Pharm. Bull. 52 (2004) 972–973; DOI: 10.1248/cpb.52.972.
5. S. W. Jong, T. S. Kim, J. H. Park, and S. C. Chi, Formulation and biopharmaceutical evaluation
of silymarin using SMEDDS, Arch. Pharm. Res. 30 (2007) 82–89; DOI: 10.1007/BF02977782.
6. W. Wachter and H. Zeskae, Flavanolignan Preparation and their Use for Preparation of Pharmaceuticals, U.S. Pat. 5,906,991, 25 May 1999.
7. D. Voinovich, B. Perrisuiti and L. Maggaroto, Solid state mechanochemical simultaneous activation of the constituents of the Silybum marianum phytochemical complex with crosslinked polymers, J. Pharm. Sci. 3 (2008) 1–14; DOI: 10.1002/jps.21417.
8. J. B. Dressman and L. Christian, Improving drug solubility for oral delivery using solid dispersions, Eur. J. Pharm. BioPharm. 50 (2000) 47–60; DOI: 10.1016/S0939-6411(00)00076-X.
9. Y. Rane, R. Mashru, M. Sankalia and J. Sankalia, Effect of hydrophilic swellable polymers on
dissolution enhancement of carbamazepine solid dispersions studied using response surface
methodology, AAPS Pharm. Sci. Tech. 8 (2007) Article 27; DOI: 10.1208/pt0802027.
10. A. Avani and M. Renuka, Formulation development of taste-masked rapidly dissolving films of
cetirizine hydrochloride, Pharm. Tech. 33 (2009) 48–56.
11. S. J. Hwang, D. H. Won, M. S. Kim, S. Lee and J. S. Park, Improved physicochemical characteristics of felodipine solid dispersion particles by supercritical anti-solvent precipitation process,
Int. J. Pharm. 301 (2005) 199–208; DOI: 10.1016/j.ijpharm.2005.05.017.
12. United States Pharmacopoeia 24/National Formulary 19, USP Convention, Rockville 2000, p. 2235.
13. P. Costa and L. J. Manuel Sousa, Modelling and comparison of dissolution profiles, Eur. J.
Pharm. Sci. 13 (2001) 123–133; DOI: 10.1016/S0928-0987(01)00095-1.
14. J. W. Moore and H. H. Flanner, Mathematical comparison of dissolution profiles, Pharm. Tech. 20
(1996) 64–74.
15. R. P. Patel and M. M. Patel, Solid-state characterization and dissolution properties of lovastatin
hydroxypropyl-beta-cyclodextrin inclusion complex, Pharm. Tech. 2 (2007) 72–81.
16. S. Baboota, M. Dhalival and K. Kohli, Physicochemical characterization, in vitro dissolution behaviour, and pharmacodynamic studies of rofecoxib-cyclodextrin inclusion compounds: preparation and properties of rofecoxib hydroxypropyl b-cyclodextrin inclusion complex: a technical
note, AAPS Pharm. Sci. Tech. 6 (2005) 83–90; DOI: 10.1208/pt060114.
17. M. A. Khan and A. A. Karnachi, Box-Behnken design for the optimization of formulation variables of indomethacin co-precipitates with polymer mixtures, Int. J. Pharm. 131 (1996) 9–17; DOI:
10.1016/0378-5173(95)04216-4.
442
Unauthenticated
Download Date | 7/20/19 3:57 AM
D. Sonali et al.: Silymarin-solid dispersions: Characterization and influence of preparation methods on dissolution, Acta Pharm. 60
(2010) 427–443.
18. S. Torrado, P. D. Torre and S. Torrado, Preparation, dissolution and characterization of pranziquantel solid dispersions, Chem. Pharm. Bull. 47 (1999) 1629–1633; DOI: 99A1042280.
19. S. R. Vikram, M. R. Shelake, S. S. Shetty, A. B. Chavan-Patil, Y. V. Pore and S. G. Late, Enhanced
solubility and dissolution rate of lamotrigine by inclusion complexation and solid dispersion
technique, J. Pharm. Pharm. Sci. 60 (2008) 1121–1129; DOI: 10.1211/jpp.60.9.0002.
20. K. Okimoto, M. Miyake, R. Ibuki, M. Yasumura, N. Ohnishi and T. Nakai, Dissolution mechanism and rate of solid dispersion particles of nilvadipine with hydroxypropylmethylcellulose,
Int. J. Pharm. 159 (1997) 85–93; DOI: 10.1016/S0378-5173(97)00274-3.
21. M. S. Nagarsenker and M. S. Joshi, Celecoxib cyclodextrin systems: characterization and evaluation of in vitro and in vivo advantage, Drug Dev. Ind. Pharm. 31 (2005) 169–178; DOI: 10.1081/
DDC-200047795.
S A @ E TA K
^vrste disperzije silimarina: Karakterizacija i utjecaj na~ina
priprave na osloba|anje
DALWADI SONALI, SONI TEJAL, THAKKAR VAISHALI i GANDHI TEJAL
U radu je ispitivan utjecaj na~ina priprave ~vrstih disperzija silimarina na brzinu
osloba|anja. ^vrste disperzije silimarina pripravljene su pomo}u hidrofilnog polimera
HPMC E 15LV metodom gnje~enja, su{enja sprejom i koprecipitacijom. Pripravci su karakterizirani pomo}u FTIR, DSC, XRPD i SEM. Profili osloba|anja uspore|ivani su statisti~ki i pomo}u metoda koje su neovisne o modelu. FTIR i DSC studije otkrile su postojanje slabih vodikovih veza izme|u lijeka i polimera, dok su XRPD i SEM potvrdile da je
silimarin u ~vrstim disperzijama amorfan. Pobolj{ano osloba|anje u odnosu na ~isti lijek
uo~eno je ovim slijedom: koprecipitacija > su{enje sprejom > metoda gnje~enja (p < 0.05).
Iz svih pripravaka osloba|anje je bilo sporije, bez obzira na metodu priprave. Pripravci
dobiveni metodom koprecipitacije bili su stabilni, a osloba|anje silimarina iz njih bilo je
2,5 bolje u odnosu na ~isti lijek.
Klju~ne rije~i: silimarin, HPMC, ~vrste disperzije, gnje~enje, su{enje sprejom, koprecipitacija, parametri osloba|anja
Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology
Changa-388421, India
Anand Pharmacy College, Anand-388001, India
443
Unauthenticated
Download Date | 7/20/19 3:57 AM